Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma

The DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O-6-benzylguanine (O(6)BG), sensitizes tumor cells to O-6-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O-6-alkylating drugs administered together with O(6)BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O(6)BG of a patient suffering from glioblastoma. O(6)BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide ( Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide ( and presumably also other O-6-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.